Background and purpose Diabetic nephropathy (DN) is a leading cause of chronic kidney diseases (CKD) characterized by mesangial matrix expansion that involves dysfunctional mesangial cells (MCs). However, the underlying mechanisms remain unclear. This study aims to delineate the spatiotemporal contribution of adrenergic signaling in diabetic kidney fibrosis to reveal potential therapeutic target. Experimental Approach Db/db mice were used to study DN. RNA sequence analyses, western blot and immunostaining were conducted to profile gene expression in kidneys. Subcellular-localized fluorescence resonance energy transfer (FRET) biosensors determined adrenergic signaling microdomains in MCs. Rolipram, a PDE4 inhibitor, was orally administrated in db/db mice to test its impact on the kidney. Key Results Db/db mice exhibited impaired kidney function with elevated adrenergic and fibrotic gene expression, including ADRB1, PDEs, ACTA2, and TGF-β. MCs with dysregulated YAP pathway played a pivotal role in extracellular matrix secretion in DN. TGF-β up-regulated β1-adrenergic receptors (β1ARs) and α-SMA in MCs. Diminished nuclear-specific cAMP signaling in MCs by TGF-β triggered profibrotic gene transcription via reducing PKA-dependent phosphorylation of YAP. The profibrotic formation was partially alleviated by norepinephrine administration and prevented by combined treatment of norepinephrine and rolipram. In db/db mice, rolipram treatment alleviated kidney fibrosis and restored kidney filtration function. Conclusion and Implications DN impairs nuclear-localized β1AR-cAMP signaling microdomain through upregulating PDE4 expression, promoting fibrosis in MCs via PKA dephosphorylation-dependent YAP activation. Results suggest PDE4 inhibition as a promising strategy for alleviating kidney fibrosis in DN.

This brief review highlights some of the structure-activity relationships of classic serotonergic psychedelics. In particular, we discuss structural features of three chemotypes: phenethylamines, ergolines, and certain tryptamines, which possess psychedelic activity in humans. Where it is known, we point out the underlying molecular mechanisms utilized by each of the three chemotypes of psychedelic molecules. With a focus on the serotonin 5-HT2A receptor subtype, a G-protein coupled receptor known to be the primary target of psychedelics, we reference several x-ray and cryoEM structures with various ligands bound to illustrate the underlying atomistic basis for some of the known pharmacological observations of psychedelic drug actions.

Mechanopharmacology is an emerging interdisciplinary field that investigates drug action using biomechanically appropriate in vitro systems to the relevant (patho)physiology. This review outlines emerging technologies and techniques which aim to bridge the gap between mechanical cues influencing cellular biology and conventional pharmacology. We delve into the impact of mechanopharmacology on drug development in cancers and fibrotic diseases. Mechanical cues such as stretch, stiffness, circadian rhythms, fluid flow, intercellular signalling cascades and cytoskeletal structures can modulate drug interactions with molecular targets with implications for drug discovery and development. Models incorporating mechanopharmacological cues to investigate pharmacokinetics, pharmacodynamics and therapeutic outcomes are outlined. Furthermore, this review discusses innovations in the use of biomaterials and microfluidics, to enable further the emulation of the mechanical microenvironment. We advocate for the application of mechanopharmacological considerations to improve the physiological relevance of methods used in the drug discovery pipeline.

Background and Purpose: Fentanyls and nitazenes are μ opioid receptor agonists responsible for a large number of opioid overdose deaths. Here, we compared the potency, dissociation kinetics and antagonism by naloxone at the μ receptor of several fentanyl and nitazene analogues and compared them to morphine and DAMGO. Experimental Approach: In vitro assays of G protein activation and signalling and arrestin recruitment were performed. AtT20 cells expressing μ receptors were loaded with a membrane potential dye and changes in fluorescence used to determine agonist potency, dissociation kinetics and susceptibility to antagonism by naloxone. BRET experiments were undertaken in HEK293T cells expressing μ opioid receptors, to assess Gi protein activation and β-arrestin 2 recruitment. Key Results: The rate of agonist dissociation from the μ receptor varied, with morphine, DAMGO, alfentanil and fentanyl dissociating rapidly whereas isotonitazene, etonitazene, ohmefentanyl and carfentanil dissociated slowly. Slowly dissociating agonists were more resistant to antagonism by naloxone. For carfentanil, the slow rate of dissociation was not due to G protein receptor kinase-mediated arrestin recruitment as its rate of dissociation was not affected by inhibition of GRKs with Compound 101. The in vitro relative potencies of fentanyls and nitazenes compared to morphine were much lower than that previously observed in in vivo experiments. Conclusions and Implications: With fentanyls and nitazenes, that slowly dissociate from the opioid receptor, antagonism by naloxone is pseudo competitive. In overdoses involving fentanyls and nitazenes higher doses of naloxone may be required for reversal than those normally used to reverse heroin overdose.

Background and Purpose: Fibroblast Growth Factor (FGF), VEGFR2, and CSF1R signalling pathways play a key role in the pathogenesis of multiple sclerosis (MS). Selective inhibition of FGFR by infigratinib in MOG35-55-induced EAE prevented severe first clinical episodes by 40%; inflammation and neurodegeneration were reduced, and remyelination was enhanced. Multi-kinase inhibition of FGFR1-3, CSF1R and VEGFR2 by AZD4547 may be more efficient in reducing inflammation, neurodegeneration and regeneration in the disease model. Experimental Approach: Female C57BL/6J mice were treated with AZD4547 (6.25 mg kg-1 or 12.5 mg kg-1) orally or placebo over 10 days either from time of EAE induction (prevention experiment) or onset of symptoms (suppression experiment). Effects on inflammation, neurodegeneration and remyelination were assessed at the peak of the disease (day 18/20 p.i.) and the chronic phase of EAE (day 41/42 p.i.). Key Results: In the prevention experiment, treatment with AZD4547 prevented severe first clinical episodes by 66.7 or 84.6% respectively. Mice treated with 12.5 mg kg-1 of AZD4547 hardly showed any symptoms in the chronic phase of EAE. In the suppression experiment, treatment with AZD4547 resulted in a long-lasting reduction of severe symptoms by 91 or 100%. Inflammation and demyelination were reduced, and axonal density, numbers of oligodendrocytes and their precursor cells, and remyelinated axons were increased in both experimental approaches. Conclusion and Implications: Multi-kinase inhibition by AZD4547 in a well-tolerated dose of 1 mg kg-1 in humans may be a promising approach to reduce inflammation and neurodegeneration, to slow down disease progression and support remyelination in patients.

Background and Purpose Thrombo-inflammation is a key feature of stroke pathophysiology and provides multiple candidate drug targets. Thrombin exerts coagulation-independent actions via protease-activated receptors (PAR), of which PAR1 has been implicated in stroke-associated neuro-inflammation. The role of PAR4 in this context is less clear. This study examined if the selective PAR4 antagonist ML354 provides neuroprotection in experimental stroke and explored the underlying mechanisms. Experimental Approach Mouse primary cortical neurons were exposed to oxygen-glucose deprivation (OGD) and simulated reperfusion ± ML354. For comparison, functional Ca2+-imaging was performed upon acute stimulation with a PAR4 activating peptide or glutamate. Male mice underwent sham operation or transient middle cerebral artery occlusion (tMCAO), with ML354 or vehicle treatment beginning at recanalization. A subset of mice received a platelet-depleting antibody. Stroke size and functional outcome were assessed. Abundance of target genes, proteins and cell markers was determined in cultured cells and tissues by qPCR, immunoblotting and immunofluorescence. Key Results Stroke upregulates PAR4 expression in cortical neurons in vitro and in vivo. OGD augments spontaneous and PAR4-mediated neuronal activity; ML354 suppresses OGD-induced neuronal excitotoxicity and apoptosis. ML354 applied in vivo after tMCAO reduces infarct size, apoptotic markers, macrophage accumulation and interleukin-1β expression. Platelet depletion did not affect infarct size in mice with tMCAO ± ML354. Conclusions and Implications Selective PAR4 inhibition during reperfusion improves infarct size and neurological function after experimental stroke by blunting neuronal excitability, apoptosis and local inflammation. PAR4 antagonists may provide additional neuroprotective benefits in patients with acute stroke beyond their canonical antiplatelet action.

A document by Mickaël Machicoane. Click on the document to view its contents.

Background and Purpose: Treatment of osteoarthritis (OA) pain often yields unsatisfactory results, making the search for new pain-relieving options essential. Vortioxetine, an antidepressant with a unique mechanism of action, has recently shown analgesic properties. We aimed to investigate its effects in the OA model and gain insight into the underlying molecular mechanisms. Duloxetine (a second-line drug for pain relief in OA) was studied as a reference. Experimental Approach: In the monoiodoacetate (MIA)-induced model of knee OA in rats of both sexes, pain-related behaviour was assessed in weight-bearing and von Frey tests. Antidepressants were administered orally once daily for 28 days. Gene expression of pain-related mediators (Ngf, Il-1β, Tnf-α, Bdnf, and Tac1 encoding substance P) and oxidative stress parameters were determined after completion of the treatment/behavioural testing protocol. Key results: Vortioxetine dose-dependently reduced weight-bearing asymmetry and mechanical allodynia of the paw ipsilateral to the MIA-injected knee. Duloxetine was also effective. Vortioxetine reduced the increased Ngf mRNA expression in the MIA-injected knees to the level observed in the sham-injected counterparts. It also reduced oxidative stress parameters in the affected knees, more effectively in females than in males. Duloxetine showed no effect on locally increased Ngf mRNA expression and oxidative stress. Both antidepressants decreased mRNA expression of pain-related mediators in the lumbar L3-L5 ipsilateral DRGs and spinal cords, which were upregulated in MIA-injected rats. This effect was male-specific. Conclusion and Implications: Vortioxetine may be effective against chronic pain in OA. This effect appears to be mediated, at least in part, by normalization of NGF expression in the affected joint.

RNA therapeutics are emerging as a unique opportunity to drug currently “undruggable” molecules and diseases. While their advantages over conventional, small molecule drugs, their therapeutic implications and the tools for their effective in vivo delivery have been extensively reviewed, little attention has been so far paid to the technological platforms exploited for the discovery of RNA therapeutics. Here, we provide an overview of the existing platforms and ex vivo assays for RNA discovery, their advantages and disadvantages, as well as their main fields of application, with specific focus on RNA therapies that have reached either phase 3 or market approval.

Commentary on: Activation of Nrf2 signalling pathway by tectoridin protects against ferroptosis in particulate matter-induced lung injuryWenfu Cao1, Xinrui Guo1, Xinyu Li, Dapeng Chen1*1Compartive medicine, Dalian Medical University, Dalian city, 116044, Liaoning province, China.*Corresponding author: Dapeng Chen, Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian 116044, P. R. China, Tel/Fax: +86 411 86110862; Email: [email protected]: lung injury, cell death, PM2.5, drug discovery, ferroptosisWe read with great interest the article entitled ”Activation of Nrf2 signalling pathway by tectoridin protects against ferroptosis in particulate matter-induced lung injury ” by Dong et al. in the British Journal of Pharmacology (Donget al. , 2023).The authors demonstrate that tectoridin has a therapeutic effect on particulate matter-induced lung injury (PM2.5-induced lung injury), and they believe that, this treatment mechanism is related to the inhibition of ferroptosis through targeting Nrf2. There are varying opinions regarding the future of targeted ferroptosis inhibition in the treatment of PM2.5-induced lung injury, and its clarity remains uncertain.With the rapid economic development, air pollution has emerged as the fifth most significant risk factor for all-cause mortality on a global scale, imposing a substantial economic burden. The animal model of lung injury, commonly employed in fundamental studies, involves the inhalation of PM2.5. In the case of lung injury induced by PM2.5, oxidative stress and inflammation, which are well-recognized indicators of lung injury, closely mirror the clinical symptoms of such injury. To induce severe and easily measurable markers of lung injury, mice were exposed to highly concentrated levels of PM2.5. Prolonged exposure to PM2.5 instigates the overproduction of reactive oxygen species (ROS), precipitating oxidative stress that results in apoptosis, and in more severe cases, necrosis (Zhao et al. , 2022).The signaling pathways involved in PM2.5-induced lung injury encompass cell death (apoptosis, necrosis and pyroptosis), inflammation, and increased oxidative stress(He et al. , 2021). Extensive research has factually demonstrated that compounds exhibiting anti-inflammatory and antioxidant characteristics are beneficial in alleviating PM2.5-induced lung injury. It is well known that Nrf2 activation can provide relief for lung injury through anti-inflammatory, antioxidant, and anti-apoptotic effects. Based on the current findings presented in the article by Dong et al , it is challenging to prove that tectoridin-induced treatment is directly associated with ferroptosis inhibition in PM2.5-induced lung injury. In my opinion, the conclusion should state that tectoridin administration alleviated ferroptosis in PM2.5-induced lung injury, as it remains unclear whether ferroptosis is the cause or result of PM2.5-induced lung injury. I apologize if my previous wording was not entirely accurate; it was not intended as a mere play on words, but rather an attempt at precision.Targeted inhibition of cell death, without affecting inflammation and oxidative stress, has never proven to be a satisfactory option for alleviating tissue injury. In PM2.5-induced lung injury, apoptosis is the primary form of cell death and is typically a direct consequence of excessive oxidative stress following PM2.5 exposure . However, the direct inhibition of apoptosis using caspase inhibitors has some palliative effects and is not an ideal treatment (Liu et al. , 2016).Ferroptosis, on the other hand, is a form of regulated cell death triggered by lipid peroxidation. Unlike apoptosis, it does not follow the typical apoptotic pathway and possesses immunogenic properties. The classic biochemical marker of ferroptosis is GPX4, SLC7A11, ATP5G3, and NOCA4. Metabolic disruptions in lipids, iron, and amino acids are closely associated with the activation of ferroptosis. Therefore, in this discussion, we will carefully explore the effectiveness of targeted ferroptosis inhibition in alleviating PM2.5-induced lung injury.Firstly, there is still a lack of large-scale clinical research to provide evidence for the causal relationship between ferroptosis and PM2.5-induced lung injury. Many current conclusions are obtained from animal or cell studies. While apoptosis and necrosis are the predominant cell death types in PM2.5-induced lung injury, recent studies have also reported other types of cell death, including necroptosis and ferroptosis. The association between ferroptosis and PM2.5-induced lung injury has only recently been observed, and further investigation is needed to establish the definitive causality. There are suggestions that PM2.5 may play a role in inducing death of lung epithelial cells through its influence on the balance of iron overload, lipid peroxidation, and redox reactions. However, whether ferroptosis is the main cause and promise target of PM2.5 induced lung injury requires further study. A search conducted on PubMed using the keywords ”PM2.5; acute lung injury; ferroptosis” yielded approximately 13 publications between 2021 and 2024. Unfortunately, none of these studies provide conclusive evidence supporting ferroptosis as the primary pathological mechanism or promise target of PM2.5-induced lung injury. The lack of precise and convincing experimental designs and results undermines the conclusion that inhibiting ferroptosis contributes to the alleviation of PM2.5-induced lung injury.Secondly, the utilization of solely biochemical markers of ferroptosis to ascertain the presence or participation of ferroptosis is subject to debate, as autophagy, apoptosis, and oxidative stress exhibit overlapping characteristics with ferroptosis, potentially leading to a pseudo-manifestation of ferroptosis caused by other factors. Given these considerations, conducting a comprehensive study on the essence of ferroptosis in PM2.5 induced lung injury without the involvement of additional factors becomes a challenging endeavor.Lastly, caution must be exercised when utilizing ferroptosis inhibitors due to the potential interference with the pharmacological properties of other drugs, thereby compromising the treatment objective. Studies have shown that combining anti-cancer drugs with a ferroptosis inducer enhances its anticancer efficacy. This discovery introduces a promising approach involving the combination of anti-cancer drugs with a ferroptosis inducer for tumor treatment. However, further comprehensive investigation is necessary to evaluate the application of ferroptosis inhibitors in the treatment of tumor patients with tissue injury syndrome, such as cisplatin-induced kidney injury (CP-AKI).Hu et al also reported the treatment effects of leonurine on cisplatin-induced acute kidney injury by inhibiting ferroptosis in BJP journal (Hu et al., 2022). It is likely that ferroptosis is not only a concomitant phenomenon but also a secondary event triggered by cisplatin exposure. Upon acute kidney occurrence, neutrophils are the first type of accumulated white blood cells in the kidneys. In comparison to apoptotic cells, ferroptotic cells exhibit higher immunogenicity and are capable of recruiting macrophages, which subsequently induce neutrophil recruitment. However, the results have shown that in CP-AKI, both parenchymal cells and immune cells, particularly macrophages and neutrophils, display significantly upregulated activity in the ferroptosis pathway(Chen et al., 2023). This non-specific activation poses challenges to develop targeted therapeutic strategies to alleviate CP-AKI through inhibiting ferroptosis.In conclusion, the potential for the development of ferroptosis inducers in cancer therapy holds promise. However, the effectiveness of ferroptosis inhibitors in treating PM2.5 induced lung injury or other forms of acute tissue injury remains uncertain. This correspondence should not be interpreted as a negative critique of the article by Dong et al., who have astutely observed the mitigating effects of tectoridin on ferroptosis in PM2.5-induced lung injury and have provided a probable connection between Nrf2 activation and ferroptosis inhibition. Conversely, our aim in writing this correspondence is to draw greater attention from researchers towards exploring the causal relationship between ferroptosis and acute tissue injury.AUTHOR CONTRIBUTIONSDapeng Chen: Conceptualization; Wenfu CAO, Xinrui Guo, and Xinyu Li: writing original draft; Dapeng Chen and Wenfu Cao: writing, review, and editing.CONFLICT OF INTEREST STATEMENTThe authors have no conflicts of interest to declare.ORCIDDapeng Chen: https://orcid.org/0000-0001-9838-1646REFERENCESChen Z, Li Y, Yuan Y, Lai K, Ye K, Lin Y, et al. (2023). Single-cell sequencing reveals homogeneity and heterogeneity of the cytopathological mechanisms in different etiology-induced AKI. Cell Death Dis 14 (5):318.Dong T, Fan X, Zheng N, Yan K, Hou T, Peng L, et al. (2023). Activation of Nrf2 signalling pathway by tectoridin protects against ferroptosis in particulate matter-induced lung injury. Br J Pharmacol 180 (19): 2532-2549.Hu J, Gu W, Ma N, Fan X, Ci X (2022). Leonurine alleviates ferroptosis in cisplatin-induced acute kidney injury by activating the Nrf2 signalling pathway. Br J Pharmacol179 (15): 3991-4009.Liu M, Shi L, Zou X, Zheng X, Zhang F, Ding X, et al. (2016). Caspase inhibitor zVAD-fmk protects against acute pancreatitis-associated lung injury via inhibiting inflammation and apoptosis. Pancreatology16 (5): 733-738.Zhao C, Pu W, Wazir J, Jin X, Wei L, Song S, et al. (2022). Long-term exposure to PM2.5 aggravates pulmonary fibrosis and acute lung injury by disrupting Nrf2-mediated antioxidant function. Environ Pollut 313: 120017.

Vascular smooth muscle cell (vSMC) dysfunction is a critical contributor to cardiovascular diseases, including atherosclerosis, restenosis, and vein graft failure. Recent advances have unveiled a fascinating breadth of non-coding RNAs (ncRNAs) that play a pivotal role in regulating vSMC function. This review aims to provide an in-depth analysis of the mechanisms underlying vSMC dysfunction and the therapeutic potential of various ncRNAs in mitigating this dysfunction, either preventing or reversing it. We explore the intricate interplay of microRNAs, long-non-coding RNAs and circular RNAs, shedding light on their roles in regulating key signalling pathways associated with vSMC dysfunction. Moreover, we discuss the prospects and challenges associated with developing ncRNA based therapies for this prevalent cardiovascular pathology.

Editorial. Platelet purinergic receptors and non-thrombotic diseases.Simon C. Pitchford1* and Dingxin Pan.11Pulmonary Pharmacology Unit, Institute of Pharmaceutical Science, King’s College London, London, UK.*Author for correspondence and reprint requests:Dr Simon PitchfordPulmonary Pharmacology UnitInstitute of Pharmaceutical Science5.43 Franklin Wilkins Building150 Stamford StreetWaterloo CampusKing’s College LondonLondon UKSE1 9NHPhone: +44 2078484266Fax: +44 207 [email protected]

Editorial on the themed issue:

Background and Purpose: Our previous study reported that erythroferrone (ERFE), a newly identified hormone produced by erythroblasts, responded to recombinant human erythropoietin (rHuEPO) sensitively but its dynamics was complicated by double peaks and circadian rhythm. This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics, and further determine whether early ERFE measurements can predict hemoglobin (HGB) responses to rHuEPO. Experimental Approach: By expressing recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted. To explore the role of iron in ERFE production, we monitored short-term changes of iron status after injection of rHuEPO or deferiprone (DFP). Pharmacokinetic/pharmacodynamic (PK/PD) modelling was used to confirm the mechanisms and examine the predictive ability of ERFE for long-term HGB responses. Key Results: The rRatERFE protein was successfully expressed and purified. The production of ERFE was deconvoluted and showed two independent peaks (2 h and 8 h). Transient iron decrease was observed at 4h after rHuEPO injection and DFP induced significant increases of ERFE. Based on this mechanism, the PK/PD model could characterize the complex dynamics of ERFE. In addition, the model predictions further revealed a stronger correlation between ERFE and HGB peak values than that for observed values. Conclusions and Implications: The complex dynamics of ERFE should be composited by an immediate release and transient iron deficiency-mediated secondary production of ERFE. The early peak values of ERFE, which occur within a few hours, can predict HGB responses several weeks after ESA treatment.

Biased signaling is a natural result of GPCR allosteric function and should be expected from any and all synthetic agonists. Therefore, it may be encountered in all agonist discovery projects and must be considered as a beneficial (or possible detrimental) feature of new candidate molecules. While bias is easily detected , the synoptic nature of GPCR signaling makes translation of simple in vitro bias to complex in vivo systems problematic. The practical outcome of this is a difficulty in predicting the therapeutic value of biased signaling due to the failure of translation of identified biased signaling to in vivo agonism. This is discussed in this review as well as some new ways forward to improve this translation process and better exploit this powerful pharmacologic activity.

Background and Purpose: P2X4 receptors (P2X4R) are ligand gated cation channels that are activated by extracellular adenosine 5′-triphosphate (ATP) released by neurons and glia. The receptors are widely expressed in the brain and have fractional calcium currents comparable to NMDA receptors. Although P2X4Rs were described to modulate synaptic transmission and plasticity, their involvement in shaping neuronal network activity remains to be elucidated. Exp. Approach: We investigated the effects of P2X receptors on network and synaptic level using local field potential electrophysiology, whole cell patch clamp recordings and calcium imaging in fast spiking parvalbumin positive interneurons (PVINs) in rat and mice hippocampal slices. The stable ATP analogue ATPγS, selective antagonists and P2X4R knockout mice were used. Key results: The P2XR agonist ATPγS reversibly decreased the power of gamma oscillations. This inhibition could be antagonized by the selective P2X4R antagonist PSB-12062 and was not observed in P2X4-/- mice. The phasic excitatory inputs of CA3 PVINs were one of the main regulators of the gamma power. Associational fibre compound excitatory postsynaptic currents (cEPSCs) in CA3 PVINs were inhibited by P2X4R activation. This effect was reversible, dependent on intracellular calcium and dynamin-dependent internalization of AMPA receptors. Conclusions and Implications: The results indicate that P2X4Rs are an important source of dendritic calcium in CA3 PVINs, thereby regulating excitatory synaptic inputs onto the cells and the state of gamma oscillations in the hippocampus. P2X4Rs represent an effective target to modulate hippocampal network activity in pathophysiological conditions such as Alzheimer’s disease and schizophrenia.

G protein-coupled receptors (GPCRs) are a large family of cell surface receptors that play a critical role in nervous system function by transmitting signals between cells and their environment. They are involved in many, if not all, nervous system processes, and their dysfunction has been linked to various neurological disorders representing important drug targets. In this review, we will first discuss the role of the nervous system GPCRs in the modulation of tripartite synapse function and how GPCRs control energy metabolism in the brain. We will then discuss the (patho)physiology and pharmacology of opioid, cannabinoid, acetylcholine, chemokine, and melatonin GPCRs in the nervous system. Furthermore, we will briefly report on adhesion GPCR function in nervous tissues. Finally, we will address orphan GPCRs, their implication in the nervous system function and disease, and the challenges that need to be addressed in the future to deorphanize them.

Chronic Obstructive Pulmonary Disease (COPD) is a major incurable health burden, ranking as the 3rd leading cause of death worldwide, mainly driven by cigarette smoking. COPD is characterised by persistent airway inflammation, lung function decline, and premature aging with the presence of pulmonary senescent cells. This review proposes that cellular senescence, a state of stable cell cycle arrest linked to ageing; induced by inflammation and oxidative stress in COPD, extends beyond the lungs and impacts the systemic circulation. This “spill over” of senescent cells contributes to brain inflammation and damage, increasing the risk of neurological comorbidities, such as stroke, cerebral small vessel disease, and Alzheimer’s disease. The review explores the role of cellular senescence in COPD-associated brain conditions and investigates the relationship between cellular senescence and circadian rhythm in COPD. Additionally, it discusses potential therapies, including senomorphic and senolytic treatments, as novel strategies to halt or improve COPD progression.